Biodegradable device

ABSTRACT

There is provided a device to promote healing of cut tissue members, such as nerves, tendon or muscles, within a body. The device is of hollow construction and comprises apertures into which the cut ends of the tissue members are placed and fixed, usually by a fibrin-based tissue glue. Located between the apertures is a substance to promote healing of the tissue member such as, for example, nerve growth factor. Optionally the device may be used in conjunction with the external reservoir of the substance and/or with a time-operated pump to deliver the substance to the device. The device is biodegradable and is preferably composed of watersoluble glass.

FIELD OF THE INVENTION

The present invention relates to a biodegradable device to aid healing.

DESCRIPTION OF THE RELATED ART

Advances in surgical techniques, particularly micro-surgical techniques,have enabled operations for re-joining or aligning severed nerves andblood vessels to be undertaken. However, to be successful suchoperations still rely upon the natural healing and regenerationprocesses of the body. Thus, even where the surgeon has exertedconsiderable skill in aligning nerve ends, there will be cases where theparts of nerves fail to re-join, or where the healing process is so slowthat the effector muscle has atrophied by the time that the motor nerveconnection becomes effective.

Healing, for example nerve regeneration, remains an essentiallybiological process. Even the most advanced micro-surgical techniques forrepairing damaged tissue members merely optimise the environment for thenatural process. It is now believed that micro-surgery has maximised themechanical processes for body repair, but a need still exists forenhancing the healing process still further.

Tubes have been used to repair severed nerves, but have enjoyed littlesuccess because the non-biodegradable tubes remained after theregenerating nerve had been established and impeded subsequentmaturation of the nerve.

GB-A-2,099,702 describes a structural support member for skeletal andtissue members comprised of a biodegradable glass. However, for thehealing process to be successful it is essential that the correctchemical environment is created to optimise the regeneration of thedamaged body part, whilst protecting that part from the body's owndefence system which can be activated against implanted foreign bodies.

In one aspect, the present invention provides a biodegradable device ofhollow construction having first and second apertures, each aperturebeing adapted to receive a cut end of a tissue member which is securedtherein by means of a fixant, and wherein at least part of the portionof said device between said apertures contains a substance to facilitatehealing of said tissue member.

Generally the device will be tubular. For example the device may be anopen-ended tube, the two open ends forming the apertures for receivingthe ends of the cut tissue member.

For convenience of manufacture the device may be essentially anopen-ended cylinder of uniform internal cross-section. Alternatively,the device may incorporate a reservoir portion, in which reserves of thesubstance are located. In this embodiment the device may be tubular, buthave an internal cross-section of varying diameter, for example ofincreased diameter in the portion between said apertures. To optimisethe healing together of the two cut ends secured in the device, theapertures may be arranged to face each other. However, in certaininstances this arrangement may not be essential, and the aperatures neednot be aligned.

The device of the present invention may be formed from a biodegradableglass. Such glasses are known to those skilled in the art and thecomposition of the glass may be adjusted to produce a glass compositionthat biodegrades over the period required, for example 1 to 6 months, or1 to 3 months. Desirably the products resulting from degradation of theglass are physiologically compatible.

Additionally, the glass composition may itself be used as a vehicle todeliver biologically active agents in a controlled release manner overthe period during which healing occurs. Controlled Release Glasses (CRG)are inorganic polymers, normally based on phosphates of sodium andcalcium, which have been converted into a glassy form by melting theconstituents at about 1000° C. CRGs dissolve in water completely leavingno solid residue.

The rate of dissolution can be selected by adjustment of the compositionand physical form of the CRG and is constant for as long as any of thematerial remains. The product can be produced in many physical forms; asa powder or granules, fibre or cloth, tubes, or as cast blocks ofvarious shapes.

As stated above, suitable biodegradable glasses are known in the art,but particular mention may be made of the glasses disclosed inWO-A-90/08470 of Giltech Limited. Typically, the glass compositions maycomprise:

    ______________________________________                                               Na.sub.2 O  7-33 mole %                                                  K.sub.2 O 0-22 mole %                                                         CaO 0-21 mole %                                                               MgO 0-22 mole %                                                               P.sub.2 O.sub.5 46-49 mole %                                                ______________________________________                                    

Such glass compositions may achieve solution rates of from 0.03 to 3.0mgcm⁻² hr⁻¹ in de-ionised water at 37° C.

Elements other than sodium and calcium, including most metals as theiroxides and a limited number of inorganic anions, can be included in thecomposition of the glass. These elements, which may be biologicallyactive, can then be delivered at a constant rate into an ambient aqueousmedium (for example a physiological fluid) as the CRG dissolves. Thishas found application in veterinary medicine as a means of deliveringsuch diverse substances as trace elements, anthelmintics and vaccines.Incorporation of a silver source (for example silver orthophosphate)into the Na₂ O--CaO--P₂ O₅ systems offers the possibility of producing aCRG capable of releasing silver ions over a highly defined time, intobiological systems with safety.

In the course of developments of this type the biocompatibility andabsence of toxicity of CRG based on Na₂ O--(Ca,Mg)O--P₂ O₅ with andwithout other constituents have been investigated. In applicationsdiffering as widely as use in orthodontics devices [see Savage, Brit. J.of Orthodontics 9:190-193 (1982)], and in controlled supply of Cu, Coand Zn in cattle [see Drake et al, Biochem. Soc. Trans. 13:516-520(1985)], no ill effects were observed. When CRG pellets were implantedsubcutaneously, intramuscularly and intraperitoneally in rats, sheep andcattle, reaction at the implant site was limited to a sterile fibrousencapsulation less well developed than that expected from biocompatiblesurgical materials [see Allen et al, Vet. Soc. Commun 2:78-75 (1978)].Other application of CRG in the Na₂ O--CaO--P₂ O₅ system have been foundas potential bone graft adjuncts/substitutes. No sign of cytotoxicitywas observed after soft tissue implantation in sheep [see Burnie et al,Biomaterials 2:244-246 (1981)]. In further experiments with bone no illeffects nor bioincompatibility could be detected [see Burnie et al,"Ceramics in Surgery" Ed Vincenzini, Elseveier Scientific, 1983, pages169-176; Burnie et al, J. Bone & Joint Surgery 65B(3):364-365 (1983);Duff et al, Strathclyde Bioengineering Seminars, Biomaterials inArtificial Organs, and Paul et al, Macmillan Press, 1984, pages312-317].

The glass composition may include one or more metal ions which areslowly released from the composition to facilitate healing. Mention maybe made of K, Mg, Zn, Al, Se, Si, Fe, Ag, Cu, Mn, Ce and/or Au.

In particular the glass composition may be manufactured to provide apotassium-rich environment, which may be useful in aiding healing of thetissue member, especially nerves.

The substance located in the device will be selected to facilitatehealing of the cut tissue member. The viscosity, osmolality and pH ofthe substance should therefore be chosen to be physiologicallycompatible with the type of tissue to be healed. The substance mayoptionally contain one or more physiologically active agents and mentionmay be made of growth factors (especially growth factors specific forthe type of tissue concerned, such as nerve growths factors for nervere-generation), anti-coagulants, agents to combat infections (forexample antibiotics, silver ions etc) and the like. Mention may be madeof platelet released and PDGF, Nerve growth factor, Keratinocytestimulation factors, Insulin-like growth factor, Interleukins, peptides,enzymes and other topical agents, oxygenators and free radicalscavengers, enzymes and nutritional agents such as proteins andvitamins. Optionally the surfaces of the glass device may be coated withsilicone to reduce thrombogenesis.

Over a number of years a great deal of evidence has emerged from invitro experiments to suggest that the group of substance known as `nervegrowth factors` or `nerve cell rescue factors` may enhance theregeneration process which takes place after a nerve is injured andrepaired. There are now many such substances awaiting evaluation. Someare thought to act preferentially on either motor or sensory nerves andthe potential for their use in chemically manipulating and improving theresults of surgical nerve repair is enormous. Despite at least 20 yearsof study in the laboratory little or no success has been achieved in themethod of delivery to this site of injury and also because the testswhich are used to quantify nerve repair are insufficiently sensitive toresolve the small (but most useful) benefits which growth factors maybring. For a substance to have maximal effect is must be delivered atthe site of regeneration, at an appropriate and maintained concentrationand at the time at which its effect on the growing nerve axons will bemost effective. To achieve this, delivery must be constant at the siteof injury over the growing period and diffusion away from this site mustbe insufficient for the local concentration to fall below effectivevalues. Lundborg [see G. Lundborg, Nerve Injury and Repair, 1988,Edinburgh Churchill-Livingston] has to a small extent achieved this bywrapping the site in silicon tubes containing growth factors. Howeverthere is still an inadequate concentration over time and the permanenttube constricts the growing nerve in its maturation phase. The endresult is worse rather than better and no surgeon in human practicewould contemplate a second operation to remove a silicon tube.

The biodegradable device of the present invention offers two featureswhich address these issues. First the device can be made to dissolveover a timecourse which would include the period of growth in lengthwhen growth factors could be delivered to an isolated environment butdissolution would occur before the non-growth-factor-dependant phase ofmaturation (growth in diameter). Secondly, growth factors could bedelivered into the device through a side hole by means of an osmoticpump. If the outlet silicon rubber tube is glued into the device awatertight system is effected. Using proprietary osmotic pumps, growthfactors can be delivered in appropriate constant concentration for fourweeks after repair. This encompasses the time for growthfactor-dependant regeneration. At the end of this time the device willbiodegrade and the pump and its tubing can be removed from its remotesubcutaneous site under local anaesthetic in a very small and simpleoperation. The nerve is thus left unimpeded to mature.

The substance may be any means to facilitate healing, including cellularmatrices which encourage and mechanically guide regeneration e.g. ofnerve or muscle, and/or humeral substances such as chemical growthfactors. By increasing the concentration of the supplied substance atthe site of injury and regeneration the latter may be enhanced and itsspecificity improved.

The fixant may be any means of securing the cut end of the tissue memberinto an aperture of the device. Desirably the fixant substantially sealsthe tissue member end into the aperture. Mention may be made of sutures,clips and other mechanical means, but desirably the fixant should bebiodegradable. Thus physiologically compatible "glues" may be preferred.One particular example is a fibrin-based tissue glue.

The device itself nay comprise means to secure a tissue member end in anaperture of the device. For example, the internal diameter of the devicemay decrease in the proximity of the aperture. In one preferredembodiment the device includes internal barbs which grip the tissuemember once inserted. Desirably however a physiologically acceptable"glue" is used to seal the aperture after insertion of the tissuemember. Thus the glue can be used to protect the damaged ends of thetissue member from the body's defence mechanisms.

The device of the present invention is particularly useful for enhancingthe healing of severed nerves, including individual nerve fibres as wellas nerve bundles. The device may also be of utility for aiding thehealing of tissue members such as tendons, blood vessels (especiallycapillary blood vessels), muscle fibres and ducts.

The ends of the tissue member may be inserted into the aperture of thedevice by any suitable means. For example, the aperture may be largeenough for the tissue member end to be simply placed therein; the endthen being secured by any suitable means, preferably a physiologicallyacceptable glue. However in certain circumstances it may be desirablefor the aperture to be of similar internal diameter to the externaldiameter of the tissue member. In this instance a suture, threadedthrough the device is drawn through the tissue member end which can thenbe pulled through the aperture as required.

In one embodiment the device has a semi-porous or porous region,preferably located between said aperatures. Prior to implantation thedevice is exposed to physiologically useful agents which may be taken upinto the porous or semi-porous region of the device for release afterimplantation. The agents may facilitate the healing of the tissuemember. Thus, the same device could be used to facilitate healing fordifferent types of tissue members, but will be adapted specifically foreach depending on the physiologically useful agents taken up into theporous or semi-porous region. Following implantation, saidphysiologically useful agent(s) can be injected adjacent to the implant,pass through the porous region and onto the tissue member under repair.

In a further embodiment, the device may include an opening to enableintroduction of a substance into the device before implantation and/orafter implantation. The opening may optionally also be used for exit ofthe suture pulling the end of the tissue member through the aperature.In one particular embodiment the device of the present invention may bereplenished with the substance after implantation. Thus, for example,the device could be connected to a reservoir external to the patientand/or a time-operated pump to automatically replenish the substance insaid device.

In a further aspect, the present invention provides a method tofacilitate healing of a cut tissue member, said method comprisinginserting each end of said tissue member into a separate aperturetherefor in the device of the present invention and securing the tissuemember ends into said apertures by means of a fixant.

The technique of inserting the tissue member ends, for example nerveends, into a tube and securing them there with fibrin-based tissue glueis very simple. This technique dispenses with the need for an operatingmicroscope, expensive microsurgical sutures and instruments and the needfor a trained microsurgeon. It may thus have considerable implicationsfor current surgical practice and could further extend the repair ofnerves to underdeveloped countries where at present nerve injuries maybe untreatable.

In a further embodiment the device of the present invention may be usedto test the effect of different factors on tissue healing. For examplethe device may be considered as a model system in which growth factorsmay be tested to find out whether and to what extent such factors may behelpful in promoting and directing the natural process of regeneration.

In a yet further embodiment the present invention provides a kit to aidhealing of a cut tissue member, said kit comprising a device of hollowconstruction having two apertures adapted to receive the cut ends of atissue member; said kit further comprising a physiologically acceptablefixant and a substance to aid healing of said tissue member.

The device of the present invention may also be used in vitro to promotegrowth of a tissue member; the regenerated tissue member maysubsequently be used for transplantation, for example to replace adamaged tissue member.

In a further aspect, the present invention provides a method of treatinga human or non-human animal body having a cut tissue member, said methodcomprising inserting the cut ends of said tissue member into separateaperatures of the device according to the invention. Optionally thedevice may be used in conjunction with an external reservoir of thesubstance and/or with a time operated pump to deliver the substance tothe device.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a biodegradable glass tube suitable for nerve repair.

FIG. 2 illustrates the biodegradable glass tube of FIG. 1 having arubber tubing attached thereto.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 shows a biodegradable glass tube 1 suitable for use in thepresent invention, especially for nerve repair. Tube 1 consists of ahollow, essentially cylindrical, glass body having aperatures 2, 3 atthe ends thereof. Two diametrically opposed suture holes 4,4' arelocated in tube 1, close to aperature 2. Two similar diametricallyopposed suture holes 5,5' are also located in tube 1, close to aperature3. Approximately mid-way down the length of tube 1 is an injection port6, which enables access to the interior volume of tube 1, even when tube1 is in place within a patient.

FIG. 2 illustrates a similar tube 1 to that shown in FIG. 1, havingflexible tubing 7 (for example silicone tubing) passed through injectionport 6 into the interior volume of tube 1. Tubing 7 may be connected toa pump or reservoir (not shown) containing a substance or active agentcapable of promoting healing of the body part in question. Oncesufficient healing has taken place tubing 7 may be simply removed,without disturbing tube 1.

In use, one of the ends of the damaged body part will be inserted intoaperature 2 of tube 1, optionally after trimming the end of the bodypart. A suture will then be passed through a first suture hole 4,through the end of the body part inserted through aperature 2 and outthrough suture hole 4'. The ends of the suture will then be securelyfastened. Optionally a tissue glue may then be used to seal the bodypart into the aperature 2 of tube 1.

The process described above will then be repeated with the other end ofthe damaged body part, aperature 3 and suture holes 5,5' of tube 1.

Optionally tubing 7 may be passed through injection port 6 into theinterior volume of tube 1 and an appropriate substance fed into the freespace within tube 1 to provide an environment suitable for healing thebody part. The two ends of the body part will gradually grow down theinterior of tube 1 and, on meeting will knit together. Alternatively thesubstance may be simply injected into the free volume within tube 1 byany suitable means (e.g. syringe).

For very small body parts (e.g. the sciatic nerve of rats, the commonperoneal nerve of rabbits or similarly sized body parts of otheranimals), the length of the glass tube may be 20-26 mm (e.g. 22 mm) withan outer diameter of 4-5 mm. The tube itself may have a thickness of 1-2mm (e.g. 1.2 mm) and the suture holes and injection ports may eachtypically have a diameter of 0.5-1 mm (e.g. 0.7 mm).

For slightly larger body parts, a larger dimensioned tube will berequired, and the dimensions recited above may be adapted as required.For example in sheep, a tube length of 30 mm having an outer diameter of8-9 mm and inter diameter of 7 mm, with suture hole and port diameter of1.2-1.3 mm may be sufficient.

The invention will be further described with reference to the following,non-limiting, examples.

EXAMPLE 1

All procedures were performed on rats and under sterile conditions.

1. The biceps femoris muscle was retracted. Care was taken not toinvolve the medial femoral circumflex artery which supplies thesemuscles.

2. The sciatic nerve was cut about 2 cm from the sciatic notch. (Midwaydown the nerve).

3. A biodegradable glass tube (as illustrated in FIG. 1) was cut to sizeenabling 2 mm of nerve to extend into the centre of the tube.

The glass of the tube was composed as follows:

    ______________________________________                                                   Mole %                                                             ______________________________________                                                Na.sub.2 O                                                                         32.0                                                               CaO 21.0                                                                      P.sub.2 O.sub.5 47.0                                                        ______________________________________                                    

The glass had a solution rate when annealed of 0.4 mgcm⁻² hr⁻¹ inde-ionised water at 37° C. The tube had a physiological life expectancyof approximately 40-50 days.

4. The tube was secured by either suture, clip or glue.

5. The animal was kept for over 60 days before undergoingelectrophysiological studies and microscopic analysis under anaesthesia.

6. EMG was taken to measure conduction velocity. The sciatic nerve wasexposed as in step 1 and dissected out 2 cm above the graft and 2 cmbelow. EMG was then taken at each point to determine the speed ofconduction: ##EQU1## The Extensor digitorum longus muscle was chosen forthe EMG because the nerve supply is the Deep Peroneal Nerve which is adirect tributary of the Sciatic-Common Peroneal Division.

    ______________________________________                                        Results                                                                                                   Conduction                                                                            Healing                                      Length (mm) Velocity time                                                    Type of Graft (if removed) (M/s) (days)                                     ______________________________________                                        Tube and Clip                                                                             13          4.33      46                                            Tube and Clip 24 25.26 67                                                     Tube and Clip 25 31.25 114                                                    Tube and Suture 12.5 8.06 47                                                  Tube and Suture 38 19.46 68                                                   Tube and Suture 27 31.76 68                                                   Tube and Suture 15 21.43 90                                                   Tube and Suture 18 21.18 90                                                   Tube and Suture 23 17.04 96                                                   Normal 18 36 --                                                             ______________________________________                                    

EXAMPLE 2

A further study was conducted to establish:

a) that a biodegradable glass tube (BGT) was compatible with effectivenerve repair; and

b) that the BGT was not toxic to the regenerating nerve or to thesurrounding tissue and that the BGT did not provoke a fibrotic tissuereaction or immune response likely to affect nerve regenerationadversely.

The experiments were performed in rats. The sciatic nerve was dividedand a BGT (as used in Example 1) placed over it. With the BGT pushed toone side the nerve stumps were repaired by epineurial suture. The BGTwas then placed at the repair site and fixed in place with epineurialsutures and fibrin glue. Electrophysiological and morphometricassessment was carried out at 100 days. It was found that normal nerveregeneration had taken place and that the BGT had completely dissolved.There was no sign of any adverse reaction.

EXAMPLE 3

This experiment was conducted on New Zealand large white rabbits. Ineach rabbit the common peroneal nerve was divided and repaired in theupper thigh. The tibial nerve was left intact. BGTs were all asdescribed in Example 1 and all of 1.5 cm in length. Each of the methodsof repair represented by the contents of the tube are accepted clinicaltechniques for nerve repair with the exception of the gap which was acontrol and which would not be expected to be compatible with recoveryof nerve function.

1) BGT+1 cm gap in nerve (control)

2) BGT+1 cm freeze-thawed muscle autograft (FTMG)

3) BGT+1 cm nerve autograft

4) BGT+nerve and FTMG short lengths in series to length of 1 cm

5) FTMG without tube (control).

There were 5 rabbits in each group.

Each animal was reviewed 6 months after nerve repair. Under anaesthesiathe repair site was re-exposed and the nerve was subjected to a numberof electrophysiological tests. Some of these tests have become wellestablished as a means of assessing recovery after nerve repair. Othersare new tests which are currently being evaluated in an attempt to findtests which will resolve the small but important improvements in nerveregeneration which may be expected where nerve growth factors are used.In all cases the opposite limb was used as a control.

After electrophysiological assessment, the segments of repaired andcontrol nerve were excised and processed for microscopic examination.Computerized morphometric assessment was used to measure indices ofnerve regeneration such as axon and fibre diameter and G-ratio.

In group 1 above it was surprising to find that regeneration had takenplace albeit to a limited extent. It seems likely that isolating theregenerating nerve within the tube may have improved its chances ofcrossing the gap. This result speaks well for the fact that the tubedoes not impede nerve regeneration.

In groups 2, 3 and 4 all of the indices of recovery showed comparabilitywith the best results obtained by conventional means. This means that asa supporting medium for either direct repair or repair using shortneural and FTMG grafts the BGT system performs as well as anything elsecurrently available.

Group 2 demonstrated the best results, with all groups 1, 2 and 3 givingsuccessful regeneration of the peripheral nerve. There were no signs ofneuroma in any of the groups and the BGT was completely dissolved afterthe 6 month test period.

We claim:
 1. A biodegradable device of hollow construction formed atleast in part from biodegradable glass, having first and secondapertures, each aperture being adapted to receive a cut end of a tissuemember which is secured therein by means of a fixant, wherein at leastpart of the portion of said device between said apertures contains asubstance to facilitate healing of said tissue member, and wherein meansto deliver said substance at an appropriate concentration are provided.2. A device as claimed in claim 1 being an open-ended tube, the two endsof the tube forming the aperatures for receiving the ends of the cuttissue member.
 3. A device as claimed in claim 1 having a reservoirportion to hold reserves of said substance.
 4. A device as claimed inclaim 1 wherein said glass is a controlled release glass.
 5. A device asclaimed in claim 4 wherein said glass releases silver ions in acontrolled release manner. and mixtures thereof.
 6. A device as claimedin claim 1 wherein said substance is selected from growth factors,anti-coagulants agents to combat infection, platelet releasate,interleukins, peptides (including enzymes), nutritional agents, andmixtures thereof.
 7. A device as claimed in claim 6 wherein saidsubstance includes nerve growth factor.
 8. A device as claimed in claim1 wherein a fixant is used to substantially seal the cut end of thetissue member to an aperature of said device.
 9. A device as claimed inclaim 9 wherein said fixant is a fibrin-based tissue glue.
 10. A deviceas claimed in claim 1 having internal barbs to grip the inserted tissuemember.
 11. A device as claimed in claim 1 having a semi-porous orporous region located between said aperatures.
 12. A device as claimedin claim 1 in combination with an external reservoir of said substanceand/or a time-operated pump to deliver said substance to said device.13. A kit to aid healing of a cut tissue member, said kit comprising adevice of hollow construction having two apertures adapted to receivethe cut ends of a tissue member; said kit further comprising aphysiologically acceptable fixant and a substance to aid healing of saidtissue member.
 14. A method of treating a human or non-human animal bodyhaving a cut tissue member, said method comprising inserting the cutends of said tissue member into separate aperatures of a device asclaimed in claim
 1. 15. A method as claimed in claim 14 wherein saiddevice is used in conjunction with an external reservoir of saidsubstance and/or a pump to deliver said substance to the device.